NCI scientists have identified a key molecular defect that may have important diagnostic implications in a tumor in children known as gastrointestinal stromal tumor, or GIST. Patients with pediatric GIST typically are deficient in the enzyme succinate dehydrogenase (SDH), which is essential for cell metabolism and energy production. Some tumors in patients with pediatric GIST have mutations in one of the four genes that code for SDH (SDHA, SDHB, SDHC, and SDHD—collectively termed SDHx). However, in some patients with pediatric GIST these genes do not have mutations. Research that appeared online December 24, 2014, in Science Translational Medicine showed that nearly all patients in the study had what is called epimutation of the SDHC gene. The epimutation identified was hypermethylation of the promoter (the controlling element for gene expression) of the SDHC gene, which prevents SDHC gene expression and subsequent expression of the SDHC protein. SDHC epimutation was the only molecular defect found in these children’s tumors; it has not been found in other tumor types and thus appears highly specific to GIST. Knowing about the epimutation may allow physicians to connect it to unique clinical features — for example, the epimutation may correlate with better or poorer survival.
Epimutant GIST, in contrast with SDHx-mutant GIST (no epimutation), does not seem to be heritable. This means that it is unlikely to signal the presence of a family cancer syndrome the way mutations in SDHx genes do. Most importantly, these results provide an immediate refinement of diagnoses thereby allowing clinical researchers to precisely define the tumor risk in this subset of patients and to potentially initiate clinical trials with agents which might reverse the epimutation, noted the investigators. This study was headed by Paul Meltzer, M.D., Ph.D., chief, and Keith Killian, M.D., Ph.D., staff clinician, Genetics Branch, Center for Cancer Research, NCI. The NIH Pediatric GIST clinic was an invaluable and unique resource for the study, since it brought GIST patients together, mostly children, from around the world to be seen by expert clinicians for diagnosis and treatment at the NIH Clinical Center. Due to the rarity of pediatric GIST, the researchers adapted existing genomics methods to routinely process preserved (formalin-fixed, paraffin-embedded) tissue samples to maximize the number of patients that could be included in this study.